IKK mediates ischemia-induced neuronal death.
Nature medicine 2005 Dec 1; 11(12):1322-9
Herrmann O O, Baumann B B, de Lorenzi R R, Muhammad S S, Zhang W W, Kleesiek J J, Malfertheiner M M, Köhrmann M M, Potrovita I I, Maegele I I, Beyer C C, Burke J JR, Hasan M MT, Bujard H H, Wirth T T, Pasparakis M M, Schwaninger M M
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.